Acetals and ketals of 16alpha, 17alpha-dihydroxyprogesterones



United tates Patent 3,053,836 ACETALS AND KETALS OF 1600,1704- DIHYDROXYPROGES'IERONES Josef Fried, Princeton, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed July 14, 1961, Ser. No. 124,005

9 Claims. (Cl. 260-23955) This invention relates to, and has for its objects the provisions of a method of preparing physiologically active steroids, and to the physiologically active steroids produced thereby.

In my applications, Serial No. 24,230, filed April 25, 1960, and Serial No. 753,401, filed August 6, 1958, I describe various 16,l7-cyclic acetal and ketal derivatives of steroids of the 16a,17a-dihydroXy-3,20-diketo-A -pregnene series and disclose that these compounds are physiologically active substances which possess glucocorticoid and anti-inflammatory activities. I have now found that if the A-ring of such steroids is saturated, thereby yielding corresponding 16,17-cyclic acetal and ketal derivatives of steroids of the 16a,17a-dihydroXy-3, ZO-diketopregnane series, the topical anti-inflammatory activity of the starting A -pregnene derivatives is surprisingly retained, although the systemic activity of these compounds is for all practical purposes eliminated. This discovery is unexpected, since a priori it would have been assumed that all anti-inflammatory activity, both systemic and topical, would be lost when the A-ring was saturated. Moreover, since the saturated pregnane steroids of this invention lack any significant systemic activity, they are compounds of choice for the topical treatment of such skin conditions as dermatitis, sunburn, neuroderrnatitis, eczema and anagenital pruritus. For these purposes they may be administered topically in the usual topically acceptable formulations, the dosage being adjusted for the relative activity of the particular steroid and the condition being treated.

Although the compounds of this invention include any 16,17-cyclic acetal or ketal of a 16a,17a-dihydroxy-3,20- diketopregnane steroid, the preferred compounds are those of the general formula wherein R is hydrogen, R is B-hydroxy, or together R and R is keto; X and X are hydrogen, chloro, fiuoro and R are keto; X and X are hydrogen, chloro, fiuoro or lower alkyl, at least one of the substituents X and X being hydrogen or lower alkyl; Y is hydrogen or methyl; Y is hydrogen, halogen (preferably chloro or fluoro) or lower alkyl (preferably methyl); Z is hydrogen, chloro, fiuoro, hydroxy or acyloxy; P is hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; or together with the carbon to which they are joined P and Q are cycloalkyl or mono- Patented Sept. 11, 1962 cyclic heterocyclic. Particularly preferred are compounds wherein R is hydrogen, R is [i-hydroxy or together R and R is keto; X is fluoro; X is hydrogen; Y is hydrogen; Y is hydrogen or fluoro; Z is hydroxy or acyloxy; and P and Q are each lower alkyl.

The compounds of this invention can be prepared in accordance with one method of this invention by hydrogenating the corresponding 16,17-cyclic acetal or cyclic ketal derivatives of 16a,17a-dihydroXy 3,20-diketo steroids of the A -pregnene (including the A -pregnadiene and A -pregnatriene) series. Such starting steroids are disclosed in my applications, Serial No. 24,230, filed April 25, 1960, and Serial No. 753,401, filed August 6, 1958. The reduction is accomplished by treatment with hydrogen in the presence of a hydrogenation catalyst such as a noble metal catalyst (e.g., palladium on a carrier or ruthenium on a carrier). The amount of hydrogen which will be absorbed depends of course on whether a pregnene, pregnadiene or pregnatriene is employed as the starting steroid and also on whether any of the substituents in the acetal or ketal moiety are reduced. Thus, theoretically if a pregnene is used and the steroid contains no other reducible groups one mole of hydrogen is absorbed per mole of steroid; a pregnadiene uses two moles of hydrogen per mole of steroid; and a pregnatriene, three moles of hydrogen per mole of steroid. If, however, other reducible groups are present, such as nitro groups, then additional hydrogen must be used to aifect complete reduction of the starting steroid to the desired product.

The compounds of this invention can also be prepared by catalytically reducing a free l6a,l7a-dihydroxy-3,20- diketo steroid of the A -pregnene (including the A pregnad'iene and a -pregnatriene) series and treating the corresponding 16e,l7a-dihydroxy-3,20-diketo-5a-pregnane steroid formed with an aldehyde of at least two carbon atoms or a ketone. The reduction is accomplished under the conditions stated hereinbefore by treatment with hydrogen in the presence of a hydrogenation catalyst. The formation of the acetal or ketal is preferably carried out by treating a suspension or solution of the steroid in the aldehyde or ketone (or an organic solvent, if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluene sulfonic acid and hydrochloric acid), neutralizing the acid and recovering the cyclic acetal or ketal' derivative formed. Particularly preferred as starting steroidal materials for this process are those of the general formula CHzZ wherein P and Q are as hereinbefore defined.

Among the suitable starting steroids utilizable in the tone; monocyclic carboxylic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobehzaldehyde and p-fluorobenzaldchyde), lower alkoxybenzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), dihydroxy benzaldehydes (e.g. resorcyaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g. o,p-dimethyl benzaldehyde), nitrobenzaldehydes, acylaminobenzaldehydes (e.g. N-acetylanthranilaldehyde), and cyanobenzaldehydes; monocyclic carbocyclic aromatic lower alkanals, such as phenylacetaldehyde, u-phenylpropionaldehyde, B-phenylpropionaldehy-de m-phenyl'butyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acy lamido and cyano derivatives thereof, monocyclic heterocylic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives thereof; monocyclic heterocyclic lower alkanals; l-(monocyclic carbocyclic aromatic) substituted lower alkauals, such as acetophenone, a,a,u-trifluoroacetophenone, propiophenone, butyrophenone, valerophenone, isocaprophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone), (lower -alkoxy)phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketones, hydroxy-phenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone), (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone), di(lower alkyl)- phenyl lower alkyl ketones (o,p-xylyl methyl ketone), nitrophenyl lower alkyl ketones (e.g. p-nitroacetophenone), acyla-midophenyl lower alkyl ketones (e.g. acetyl aniline, and cyanopheny-l lower alkyl ketones; benzophenone, and mono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic carbocyclic aromatic lower alka-nones, such as 1-phenyl-3-butanone and l-phenyl-4- pentanone, and aromatically substituted derivatives thereof; l-(monocyclic heterocyclic) substituted lower alkanals, such as 2-acetylfuran, 2-benzoylfuran, and 2- acetyl-thiophene; oxo substituted monocyclic heterocyclics, such as monocyclic heterocyclic lower alkanones; and X0 lower alkanoic acids such as glyoxylic, pyruvic, acetoacetic, ,B-ketopropionic, ot-ketobutyric, levulinic, ,8- ketocaproic and fi-ketocaprylic acid [as well as salts and esters thereof, such as lower alkyl esters (e.g. methyl and ethyl)].

Among the suitable 21-esters can be mentioned those which are formed with the acyl radical of: (a) a hydrocarbon rnonocarboxylic acid of less than twelve carbon atoms, such as an alkanoic acid (e.g., acetic, propionic, tert.-pentanoic, enanthic, and undecanoic acid), a monocyclic aryl carboxylic acid (e.g., benzoic and toluic acid), a monocyclic aryl lower alkanoic acid (e.g., phenacetic and B-phenylpropionic acid), a lower alkenoic acid, (e.g. undecanoic acid), a cycloalkane carboxylic acid, or a cycloalkenecarboxylic acid; (b) a hydrocarbon dicarboxylic acid of less than twelve carbon atoms, such as a lower alkanedioic acid (e.g., oxalic, malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic and sebacic acid), a lower alkenedioic acid (e.g., maleic, fumaric and citraconic acid), a cycloalkanedioic acid, a cycloalkenedioic acid, and a monocyclic aromatic dicarboxylic acid (e.g., the phthalic acids), as well as salts thereof with suitable bases such as inorganic bases, such as ammonium hydroxide, the alkali metal hydroxides (e.g., potassium hydroxide and sodium hydroxide) and the alkaline earth metal hydroxides; and organic bases, such as di(lower alkyl)amines and heterocyclic amines (e.g., pyridine); and (c) phosphoric acid.

All such starting steroids can be prepared by methods disclosed in my said applications, Sen'al Nos. 24,230 and 753,401.

The 21-esters can also be prepared from the corresponding 2l-hydroxy-5oc-pregnanes by treatment of the latter with an acyl halide (preferably acyl chloride) or acid anhydri'de of one of the hydrocarbon monocarboxylic acids of less than twelve carbon atoms mentioned hereinbefore, one of the hydrocarbon dicarboxylic acids of less than twelve carbon atoms mentioned hereinbefore, or phosphoric acid, the reaction being conducted under the usual acylating conditions.

Among the suitable starting steroids utilizable in the second process of this invention may be mentioned the free 16cc, 17a-dihydroxy steroids of the A -pregnene (including A -pregnadiene and A -pregnatriene) series listed hereinbefore. The preparation of such steroids is disclosed in my said applications, Serial Nos. 24,230 and 753,401, or in the prior art.

Among the suitable aldehydes and ketones which can be used in the second process of this invention may be mentioned those aldehydes and ketones specifically listed hereinbefore.

The following examples illustrate the invention (all temperatures being in Centigrade):

EXAMPLE 1 9a-F l IlOlO-l 6 0a,] 711- 'sopropy ZidenediOxy-Sa-Pregnane- 11,8,21-Diol-3,20-Di0ne A suspension of 3 g. of 5% palladium on barium sulfate in m1. of ethyl acetate is agitated in an atmosphere of hydrogen until hydrogen is no longer absorbed ml.). To this suspension is added a suspension of 10 g-. of triamcinolone 16,17-acetonide in 900 ml. of ethyl acetate and the mixture agitated until hydrogen is no longer absorbed (1200 ml.). Filtration of an aliquot and evaporation to dryness furnishes material which shows an of 18.4 at 238 m indicating the presence of unreduced triamcinolone acetonide. The total mixture is therefore filtered, washed well with ethyl acetate and hydrogenated again for 24 hours with 3 g. of fresh palladium on barium sulfate catalyst. Eighty-seven milliliters of hydrogen are taken up. The mixture is filtered and the solvent removed, in vacuo. The ultraviolet spectrum of this material has lli...

of 2.5 at 296 me and a minimum at 238 m The crude residue on recrystallization from acetone-hexane furnishes analytically pure material in almost uantitative yield possessing the following properties: M.P. about 2l-l-213 and 240243; [a] +77 (0., .66 in chlf.) Ami? 2.70, 2.89, 3.05, 5.76, 5.85 A212,; 296 m (Elfi 2.48)

Ana lysis.-Calcd. for C I-1 0 1 (440.53): C, 65.43; H, 8.46. Found: C, 65.44; H, 8.08.

EXAMPLE 2 Following the procedure of Example 1 but substituting 10 g. of 9a-fluoro-l6ot-hydroxyhydrocortisone 16,17- acetonide for the triamcinolone acetonide, the same product is formed in quantitative yield.

EXAMPLE 3 Following the procedure of Example 1' but substituting 10 g. of 9a-fluoro-A -pregnatriene-11 3,1'6a,17a-21- tetrol-3,20-dione 16,17-acetonide for the triamcinolone acetonide, the same product is formed.

EXAMPLE 4 9a-Flworo-l 6a,] 7w (2'-Bwtylia'enedi0xy Jet-Pregnanc- 1I[i,21-di0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16a,17a-(2-butylidene) triamcinolone for the triamcinolone acetonide, 9a-fiuoro-16a,17a-(2-butylidenedioxy)-5a-pregnane-11B,21-diol-3,2O dione is obtained.

7 EXAMPLE 5 Following the procedure of Example 1 but substituting 10 g. of 16a,17u-(4'-methyl-2'-pentylidene) triamcinolone for the triamcinolone acetonide, 9ot-fluoro-16a,17u-(4'- methyl-2-pentylidenedioxy) -5 a-pregnane 11,8,21-dio1-3, ZO-dione is obtained.

EXAMPLE 6 9a-Flll0r0-l6u,1 7a-Cycl0l1exylidenedioxy-S oc- Pregnane-Il 5,21 -Dil-3,20-Dione Following the procedure of Example 1 but substituting 10 g. of 1611,170t-CYClOh6XY1ld6H6 triarncinolone for the triamcinolone acetonide, 9a-fiuoro-l6a,l7ot-cyclohexylidenediOXy-Sa-pregnene-I1,8,21-diol-3,20-dione is obtained.

EXAMPLE 7 9a-Fluor0-1 6 (1,1 7a-(3-Pentylidenedioxy a- Pregnane-11/3,21-Di0l-3,20-di0ne Following the procedure of Example 1 but substituting g. of 16u,17a-(3-pentylidene) triamcinolone for the triamcinolone acetonide, 9a-fluoro-16a,17oc-(3'-pentylidenedioxy)-5a-pregnane-11,8,21-diol 3,20 dione is obtained.

EXAMPLE 8 9et-FIllOl0-16a,1 7ot-Ethylidenedi0xy-5a-Pregnane-115,21-

Dial-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16u,17a-ethylidene triamcinolone for the triamcinolone acetonide, 9e-fluoro-16e-17a-ethylidenedi0xy- 5a-pregnane-l1,8,21-diol-3,20-di0ne is obtained.

EXAMPLE 9 9a-FIll0I'0-1 6 01,1 7a-Is0pr0pylidenediOxy-Sa-Pregnane- 21-OI-3,I1,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of 9u-fll1010-16oc-hYdt0XYCOItlSOI16 16,17-acetonide for the triamcinolone acetonide, 9a-fluoro-16a,17ot-isopropylidenedioxy5a-pregnane-2l-ol-3,l1,20-trione is obtained.

EXAMPLE 1O 1 6 a,] 7a-Cycl0hexylidenedioxy-5a-Pregn (me-1 15,21- Dial-3,20-D ione EXAMPLE 11 1 6 41,1 7tx-Is0pr0pylidenedioxy-Su-Pregnane-I 1 13,21

Dial-3,20-Di01ze Following the procedure of Example 1 but substituting 10 g. of l6ot,l7ot-isopropylidene 16a-hydroxyprednisolone for the triamcinolone acetonide, 16a,17a-isopropylidenedioxy-5a-pregnane-11,8,21-diol-3,20-dione is obtained.

EXAMPLE 12 1 6a,] 7a-(3-Pentylidenedi0xy -12ot-Chloro-Su-Pregnane- 21-Ol-3,11,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of l6a,l7a-(3-pentylidene) IZa-ChlOlO-lGu-hY- droxycortisone for the triamcinolone acetonide, l6ot,17et- (3'-pentylidenedioxy) 12a chloro 5u-pregnane-21-ol- 3,11,20-trione is obtained.

EXAMPLE 13 Following the procedure of Example but substituting 10 g. of 16a,17ot-isopropylidene 16u-hydroxy-12a-fluorohydrocortisone for the triamcinolone acetonide, 16a,l7aisopropylidenedioxy 12u-fluoro-5a-pregnane-1113,2l-diol- 3,20-dione is obtained.

EXAMPLE l4 12a-Fllt0r0-16a,1 7 oc-lsopropylid ened ioxy-5 a-Pregnane- 1 Ifi-OZ-iZO-Dione Following the procedure of Example 1 but substituting 10 g. of l6a,17ot-isopropylidene 12a-fluoro-A -pregnenel15,16a,17e-triol-3,20-dione for the triamcinolone acetonide, 12ct-fluoro-l6a17ot-isopropylidenedioxy-5tit-pregnanc- 11fi-0l-3,20-dione is obtained.

EXAMPLE l5 1 6 0a,] 711- (3'-Pentylidenedi0xy -1Za-Chl0r0-5a-Pregnane- 11/3-Ol-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16a,17a-isopropylidene 9a-fiuoro-A -pregnene- 11 [3,16a,17a-triol-3,20-dione for the triamcinolone acetonide, c fluoro 1611,1711 isopropylidene-dioxy-5a-pregnane-ll/i-ol-3,20-dione is obtained.

EXAMPLE 16 Following the procedure of Example 1 but substituting 10 g. of 16u,17a-isopropylidene 6u-methyl-l6a-hydroxyprednisolone for the triamcinolone acetonide, Got-methyll6ot,l7m-isopropylidenedioxy 5ot-pregnane-llfl,2l-diol- 3,20-dione is obtained.

EXAMPLE 17 Following the procedure of Example 1 but substituting 10 g. of 16ot,17a-isopropylidene 6a-methyl-9ut-fluoro-l6aliydroxyprednisolone for the triamcinolone acetonide, 6c:- methyl 90c fluoro-16a,17a-isopropylidenedioxy-5a-pregname-11fi,2l-diol-3,20-dione is obtained.

EXAMPLE 18 Acetophenone Derivative 0f 9a-Fluoro-5a-Pregnane- 1Ifl,16ct,1704,21-Telr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of triamcinolone for the triamcinolone acetonide, the acetophenone derivative of 9a-fluoro-5a-pregnane-l1,8,16a,17e,21-tetrol-3,20-dione is obtained.

EXAMPLE 19 p-A minoacetophenone Derivative 0 f 9nt-Fluoro-5a- Pregnane-J 1 5,1 6 0a,] 7 a,21 -T etr0l-3 ,2 O-Dione Following the procedure of Example 1 but substituting 10 g. of the p-nitroacetophenone derivative of triamcinolone for the triamcinolone acetonide, the p-aminoacetophenone derivative of 9a-fluoro-5a-pregnane-115,1611,- l7a,21-tetrol-3,20-dione is obtained.

EXAMPLE 20 Acetophenone Derivative 0f 9a-FIuor0-5a-Pregnanea,] 7a,21-Tri0l-3,11,20-Trione Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of 9a-fluoro-l6ahydroxycortisone for the triamcinolone acetonide, the acetophenone derivative of 9u-fluoro-5a-pregnane-l6a,- l7u,21-tl'l0l-3,11,20-l1i0116 is obtained.

9 EXAMPLE 21 Benzaldehyde Derivative of Sa-Pregnane-J]fl,16a,17a,21- T etrl-3 ,2 0-D ione Following the procedure of Example 1 but substituting 10 g. of the benzaldehyde derivative of 16a-hydroxyhydrocortisone for the triamcinolone acetonide, the benzaldehyde derivative of Sa-pregnane -11 fl,16a,l7ot,21-tetrol- 3,20-dione is obtained.

EXAMPLE 22 F urfural Derivative of ix-Pregnane-11B,16a,17ot,21-

Tetr0l-5',20-Di0ne Following the procedure of Example 1 but substituting g. of the furiural derivative of l6a-hydr0xyprednisolone for the triamcinolone acetonide, the fur-fural derivative of 5ot-pregnane-ll5,l6a,17u,2l-tetrol-3,20 di0ne is obtained.

EXAMPLE 23 Benzophenone Derivative 0f 12oc-Chl0r0-5 oi-Pregnane- 16a,I7a,21-Tri0l-3,11,20-Tri ne Following the procedure of Example 1 but substituting 10 g. of the benzophenone derivative of 12a-chloro-l6ahydroxycortisone for the triamcinolone acetonide, the benzophenone derivative of 12a-chloro-5a-pregnane-16a,- 17a,21triol-3,l1,20-trione is obtained.

EXAMPLE 24 Acetophenone Derivative 0 f 12oi-Flu0r0-5 a-Pregnane- 1],B,16oi,1 7a,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of 12a-flUOIO-16ahydroxyhydrocortisone for the triamcinolone acetonide, the acetophenone derivative of 12a-fluoro-5a-pregnanel 1,8,16a,21-tetrol-3,20-dione is obtained.

EXAMPLE 25 2-A cety ifaran Derivative of 1 2 a-FIuOrO-Sa-Pregnane- 11,6,16a,17a,21-Tetrol-3,20-Dione Following the procedure of Example 1 but substituting 10 g. of the 2-acetylfuran derivative of 12a-fiuoro-16ahydroxyprednisolone for the triamcinolone acetonide, the 2-acetylfuran derivative of l2a-fluoro-5 -pregnane-1118, 16a,17u,2l-tetrol-3,20-dione is obtained.

EXAMPLE 26 p-Aminoacetophenone Derivative of 9ot-Flu0r0-5oi- Pregnane-11/3,16a,1 7a,Tri0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the p-nitroacetophenone derivative of 9oc-fltl0l0- M-pregnene-lldfld6u,l7u-triol-3,20'-dione for the triamcinolone acetonide, the p-arninoacetophenone derivative of 9a-fluoro-Sa-pregnane-1:15,l6a,17a-triol-3,20-dione is obtained.

EXAMPLE 27 Acetophenone Derivative of 6 -Methyl-5u-Pregnane- 11,B,16a,1 70,21 -Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of 6a-In6thYl-l6oahydroxyprednisolone for the triamcinolone acetonide, the acetophenone derivative of 6a-methyl-5a-pregnane-11(3, 160a,17oc,21-t6t1Ol-3,20dl0i1e is obtained.

EXAMPLE 28 Following the procedure of Example 1 but substituting 10 g. of acetophenone derivative of 9a-fiUOIO-6ot-I1'16thYl- 16ot-hydroxyprednisolone for the triamcinolone acetonide, the acetophenone derivative of 9a-fiuoro-6ot-methyl-5a pregnane-llfi,16a,17a,21-tetrol-3,20-dione is obtained.

1t EXAMPLE 29 9a-Chl0I0-1 6a,] 7 a-Isopropylidenedioxy-S u-Pregnane- 1],B-Ol-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16a,17a-isopropylidene cCl1lOIO-l1fi,16a,17ol. trihydroxyprogesterone for the triamcinolone acetonide, 9a-chloro-16a,17a-isopropylidenedioXy-Sa-pregnane 11 3- ol-3,20-dione is obtained.

EXAMPLE 30 QOt-FII/ OI'O-I 6 11,1 7a-Is0pr0pyiidenedioxy-Sot-Pregnane- 3,11,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of 16a,l7a-isopropylidene 9a-fluoro-A -pregnene- 16a,17a-CliOl-3,l1,20-t1i01'16 for the triamcinolone acetonide, 9a,fluoro-16a,17a-isopropylidenedioxy Set-pregnanc- 3,11,20-trione is obtained.

EXAMPLE 31 904-672 lore-1 6 04,1 7u-Is0pr0pyliden ed i0xy-5 a-Pregnane- 3,1 1,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of 16a,17a-isopropylidene 9a-chloro-A -pregnenei,17oL-(liOl-3,11,20ifi01'16 for the triamcinolone acetonide, 9oc-ChlOIO-1 6a, 17wisopropylidenedioxydot-pregnane- 3,11,20-trione is obtained.

EXAMPLE 32 1600,] 7a-Chl07al Derivative of Qa-FIuOrO-Sa-Pregnane- 11/3,]6a,]7a,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the l6a,l7oi-chloral derivative of triamcinolone for the triamcinolone acetonide, the 16a,17a-chl0ral derivative of 9a-fiuoro-5a-pregnane-11B,16a17u,21-tetrol-3, 20.-dione is obtained.

EXAMPLE 33 T riflitoroacetonide of QwFIaOrO-Sa-Pregriane-I1 8,16a, 17u,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the trifiuoroacetonide of triamcinolone for the triamcinolone acetonide, the trifluoroacetonide of 9afluono-S a-pregnane-l l [3,16cc,17oc,21-t61013,20di0116 is obtained.

EXAMPLE 34 EXAMPLE 35 Following the procedure of Example 1 but substituting 10 g. of 1,1,1-trifluoroacetonide of 16a-hydroxyhydrocortisone for the triamcinolone acetonide, 1,1,1-trifluoroacetonide of Sa-pregnane-l1,6,16a,17u,21-tetrol-3,20-dione is obtained.

EXAMPLE 36 H eptafluorob atanal Derivative of 9o -Fluoro-5a-Pregnane 115,16a,]7a,21-Tetr0l-3;20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the heptafluorobutanal derivative of trimacinolone for the triamcinolone acetonide, the heptafiuorobutanal derivative of 9or-lluoro-Swpregnane-111ti,16 t,-17a,2l-tetro1 3,20-dione is obtained.

1 1 EXAMPLE 37 1 6 a,1 7u-Chl0ral D erivative of 1 2u-Chloro-5a-Pregnan e- 160a,] 711,21-TriI-3,11,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of the l6a,l7a-chloral derivative of 12u-Ch101'O-16cc, hydroxycortisone for the triamcinolone acetonide, the 160:, Uni-chloral derivative of 12a chloro a-pregnane-16a 17a,21-triol-3,11,20-trione is obtained.

EXAMPLE 3 8 160a,] 7a-Chl0ral Derivative of IZa-Fluoro-Sa-Pregnane- 11 3,16a,1 7a,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting g. of the 16a,17a-ch1oral derivative of 12a-fluoro-16ahydroxy hydrocortisone for the triamcinolone acetonide, the 16a,17a-chloral derivative of l2a-fiuoro-5a-pregnane- 115,16u,17a,2l-tetrol-3,20-dione is obtained.

EXAMPLE 39 16a,l7a-Chloral Derivative of IZa-FIimrO-Sa-Pregnane- 1 1/3,16a,1 7a-Triol-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the 160:,17oz-Chl0ffll derivative of 12a-fluor0-A pregnene-l1 8,l6a,17a-triol-3,20-dione for the triamcinolone acetonide, the 16a,17 x, chloral derivative of 12a-fluoro-5a-pregnane-11,8,16a,17a-tri0l-3,20 dione is obtained.

EXAMPLE 40 1 ,1,1-Triflu0r0acelonide of 6u-Methyl-5u-Pregnane-J1p, 1611,] 7oc,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10g. of 6u-methyl-1fiu-hydroxyprednisolone 1,1,1-trifluoroacetonide for the triamcinolone acetonide, the 1,1,1-

trifiuoroacetonide of 6u-methyl-5u-pregnane-ll/3,16u,17a, 2l-tetrol-3,20-dione is obtained.

EXAMPLE 41 1,1,1-Triflu0r0acetonide of 6 a-M ethyl-Qa-F luoro-S a- Following the procedure of Example 1 but substituting 1,l-.trifluoroacetonide for the triamcinolone acetonide, the

EXAMPLE 42 9a-Metl1yl-16a,]7a-Is0pr0pylia'enedioxy-Sa-Pregnane- 11fl,21-Di0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 160:,l7ot-iSOPI'OPYlld6I16 9a-methyl-l6a-hydroxyprednisolone for the triamcinolone acetonide, 9a-methy1- 16a,17a-isopropylidenedioxy-5u pregnane 115,21-diol- 3,20-dione is obtained.

EXAMPLE 43 1 Za-M ethy l-] 6 0a,] 7a-I s0 propy lia'enedioxy-S rx-Pregnane- 11j3,21 -Diol-3,20-Di0ne Following the procedure of Example 1 but substituting 10g. of 160:,17cc-iSOPIOPYlld6IlC 12a-methy1-16a-hydroxyprednisolone for the triamcinolone acetonide, IZOL-ITIElZlJYl- 16a,17u-isopropylidenedioxy-5a pregnane 115,21-di01- 3,20-dione is obtained.

EXAMPLE 44 9a-Mehtyl-16a,17a (2'-Buzylidenedioxy -5a-Pregnane- 21-01-3, 11,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of 16a,17u-(2'-butylidene) 9a-rnethyl-16ahydroxycortisone for the triamcinolone acetonide 9a-rnethyl-16u,

EXAMPLE 47 9a-Methyl-16a,17a-Ethylidenedi0xy-5u-Pregnane-1 I19, 21-Di0l-3,20-Dione Following the procedure of Example 1 but substituting 10 g. of 16a,17a-ethylidene 9a-methyl-16u-hydroxyprednisolone for the triamcinolone acetonide, 9a-methyl'16tz, 17a-ethylidenedioxy-5u-pregnane-l118,21 diol-3,20-dione is obtained.

EXAMPLE 48 12a-Methyl-16a,17a-Is0pr0pylidenedi0xy-5u-Pregnane- 11;3-Ol-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16a,l7a-isopropylidene IZa-methyl-M-pregnem- 11fl,l6a,l7u-triol-3,20-dione for the triamcinolone acetonide, l2a-methyl-l6a,17a-isopropylidenedioxy 5a pregnane-l l,B-ol-3,20-dione is obtained.

EXAMPLE 49 Acetophenone Derivative of 9a-Methyl-5a-Pregnane- 11,6,16oc,1 7uc,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10g. of the acetophenone derivative of 9u-methyl-16ahydroxyprednisolone for the triamcinolone acetonide, the acetophenone derivative of 9a-methyl-5a-pregnane-11p, 16a,17u,21-tetrol-3,20-dione is obtained.

EXAMPLE 5 O Acetophenone Derivative of 9a-Methyl-5a-Pregnane- J ];8,16a,] 7a,21-Tetr0l-3,20-Dione 21-Acetate Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of 9oc-I118tl1yl-l6ochydroxyprednisolone 21-acetate for the triamcinolone acetonide, the acetophenone derivative of 9u-methyl-5apregnane-l113,l6oi,21-tetrol-3,20-dione 21-acetate is obtained.

EXAMPLE 51 Benzaldehyde Derivative 0f 9a-Methyl-Sa-Pregnane-l1/3, 1601,170c, 21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the benzaldehyde derivative of 9a-methyl-l6ahydroxyhydrocortisone for the triamcinolone acetonide,

the benzaldehyde derivative of 9a-methyl-5u-pregnane- 11/3,l6a,17u,2l-tetrol-3,20-dione is obtained.

EXAMPLE 52 F urfural Derivative of 12a-MethyI-Sa-Pregnane-I1/3, 16oz,17a,21-Ttr0l 3,20-Di0ne Following the procedure of Example 1 but substituting 13 10 g. of the furfural derivative of 12a-methyl-16a-hydroxyprednisolone for the triamcinolone acetonide, the furfural derivative of 12e-methyl-5mpregnane-1113,16a, 17a,21-tetrol-3,20 -dione is obtained.

EXAMPLE 5 3 Benzophenone Derivative IZQt-MethyZ-Su-Pregnane- 16 11,1 70:,21-Tri0l-3,11,20-Tri0ne Following the procedure of Example 1 but substituting 10 g. of the benzophenone derivative of l2a-methyl-16ahydroxycortisone for the triamcinolone acetonide, the benzophenone derivative of IZa-methyl-Sa-pregnane-l6a, 17 a,21-triol-3,11.20-trione is obtained.

EXAMPLE 54 2-14. cetylfaran Derivative of 12 a-Methyl-u-Pregnane- 11fl,16a,17a,21Tetrol-3,20-Di0ne Following the procedure of Example 1 but substituting g. of the 2-acetylfuran derivative of 12a-methyl-l6ahydroxyprednisolone for the triamcinolone acetonide, the Z-acetylfuran derivative of 12a-methyl-5a-pregnane-11B, 16a,17a,21-tetr0l-3,20-dione is obtained.

EXAMPLE 55 Ethyl Levulinate Derivative of 9oc-Fluoro-5a-Pregnane- 1lB,16a,17a,21-Tetrol-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the ethyl levulinate derivative of triamcinolone for the triamcinolone acetonide, the ethyl levulinate derivative of 9a-fluoro-5a-pregnane-l lfl,16u,17a,21-tetrol- 3,20-dione is obtained.

EXAMPLE 56 Levalinic Acid Derivative of 9a-Flu0ro-5a-Pregnane- 1113,1604] 7a,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the levulinic acid derivative of triamcinolone acetonide, the levulinic acid derivative of 9cz-fluOIO-5ccpregnane-ll5,16a,17a,2l-tetrol-3,20-dione is obtained.

EXAMPLE 57 Sodium Levalinate Derivative 0 f 9a-Flu0r0-5a-Pregnane- 1 ]/3,16a,1 7a,21-Tetrol-3,20-Dione Following the procedure of Example 1 but substituting 10 g. the sodium levulinate derivative of triamcinolone for the triamcinolone acetonide, the sodium levulinate derivative of 9a-fluoro-5a-pregnane-11/3,16a,17a,21-tetrol- 3,20-dione is obtained.

EXAMPLE 5 8 Methyl Glyoxylate Derivative 0] 9a-Flaoro-5a-Pregnane- 11,8,16a,17a,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the methyl glyoxylate derivative of triamcinolone for the triamcinolone acetonide, the methyl glyoxylate derivative of 9u-fluoro-5a-pregnane-11,8,16a,17a,21-tetrol- 3,20 -dione is obtained. 1

EXAMPLE 59 Ethyl Acetoacetate Derivative of 5 a-Pregnane- 11,8,16a,17a,21-Tetr0l-5,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the ethyl acetoacetate derivative of 16a-hydroxyhydrocortisone for the triamcinolone acetonide, the ethyl acetoacetate derivative of Sa-pregnane-llB,l6a,17a,21- tetrol-.3,20-dione is obtained.

EXAMPLE 60 Ethyl Levulinate Derivative of 5 a-Pregnane- 1118,16a,17a,21-Tetrol-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the ethyl levulinate derivative of l6zx-hYd1'OXY- i l prednisolone for the triamcinolone acetonide, the ethyl levulinate derivative of SaHpregnane-I 1fi,160c,17a,21-t6t1'01- 3,20-dione is obtained.

EXAMPLE 61 Ethyl Levalinate Derivative of 1Za-Chloro-5a-Pregnanee,]7u,21-Tri0l-3,11,20-Trione Following the procedure of Example 1 but substituting 10 g. of the ethyl levulinate derivative of 12a-chloro-16ahydroxycortisone for the triamcinolone acetonide, the ethyl levulinate derivative of 1Za-chlOro-Suregnane-16a, l7a,2 1-triol-3,11,20-trione is obtained.

EXAMPLE 62 Ethyl Levalinate Derivative of 12a-Flu0r0-5a-Pregnane- 1 15,] 6a,] 7a,21-Tetr0l-3,20-Dione Following the procedure of Example 1 but substituting 10 g. of the ethyl levulinate derivative of 12oc-flu0I'O-16n4, hydroxyprednisolone for the triamcinolone acetonide, the ethyl levulinate derivative of 12a-fluoro-5a-pregnane-1 1B, 16a,l7a,21-tetr0l-3,20-dione is obtained.

EXAMPLE 63 Ethyl Pyruvate Derivative of 12a-Flu0ro-5a-Pregnane- 11,6,1 6a,17a-Triol-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the ethyl pyruvate derivate of 12a-fiuoro-A pregnene-l1,8,16a,l7a-triol-3,20-dione for the triamcinolone acetonide, the ethyl pyruvate derivative of 12oi-fluoro- Sa-pregnane-I113,16a,17a-triol-3,20-dione is obtained.

EXAMPLE 64 Ethyl Levulinate Derivative of 6 will ethyl-5 a-Pregnane- 11,6,16a,17a,21-Tetrol-3,20-Dione Following the procedure of Example 1 @but substituting 10 g. of the ethyl levulinate derivative of 60c-Ill8thYl-160thydroxyprednisolone for the triamcinolone acetonide, the ethyl levulinate derivative of 6oi-methyl-5a-pregnane-11B, 16a,l7a,2l-tetrol-3,20-dione is obtained.

EXAMPLE 65 Ethyl Levulinate Derivative 0 f 6 a-M ethy l-9a-F l a0r0-5 a- Pregnaize-1Jp,16u,1 7 0:,21 -Tetr0l-3,20-Di0ne 9a-F luoro-J 6 (1,1 7 a-ISO propy lidenedioxy-S a-Pregnane- 1]fl,21-Di0l-3,20-Di0ne 21-Acetate Following the procedure of Example 1 but substituting 10 g. of triamcinolone acetonide ZI-acetate for the triamcinolone acetonide, 9a-fluoro-l6a,l7a-isopropylidenedioxy 50c pregnane-l l 13,21-di0l-3,20-dione 21-acetate is obtained.

EXAMPLE 67 Acetophenone Derivative of 9a-Flu0r0-5u-Pregnane-11,9, 16a,17a,21-Tetr0l-3,20-Di0ne 21 -Acetate Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of triamcinolone 21 acetate for the triamcinolone acetonide, the acetophenone derivative of 9a-fluoro-5a-pregnane-1lp,l6a,17u,21-tetrol- 3,20-dione 2l-acetate is obtained.

EXAMPLE 68 16a,17a-Chl0ral Derivative of 9oc-Flll0J0-5w-Pfiglldfl8- 11,8,16a,17a,21-Tetr0l-3,20-Di0ne 21 -H emisuccinic Acid Following the procedure of Example 1 but substituting 10 g. of the 16,17-chloral derivative of triamcinolone 21 hemisuccinic acid for the triamcinolone acetonide, the 16a,17a-ch1oral derivative of 9a-fluoro-5a-pregnane-11 6, 16a,17a,21-tetrol-3,20-dione 2l-hemisuccinic acid is obtained.

EXAMPLE 69 Ethyl Levulinate Derivative f 9a-Fluoro-5a-Pregnane- 11}9,16a,1 7a,.21-Telrol-3,20-Dione 21 -A cetate Following the procedure of Example 1 but substituting g. of the ethyl levulinate derivative of triamcinolone 2l-acetate for the triamcinolone acetonide, the ethyl levulinate derivative of 9OL-fll1OI0-5tZ-PI6gIlal'l6-11,3,1601, 17a,21-tetrol-3,20-dione ZI-acetate is obtained.

EXAMPLE 7O (a) Preparation of 9a-flu0r0-16a,]7a-isopropylidenedi- Oxy-Sa-pregnane-J1 3,21-di0l-3,20-di0ne 21 -hemisuccinic acid.-A solution of 4 g. of 9a-fluoro-16a,17a-isoproplyidenedioxy-Sa-pregnane-l1 3,21-diol-3,20-dione and 8 g. of succinic anhydride in 40 ml. of anhydrous pyridine is heated at 60 for two hours. After cooling to g. of ice is added and the mixture poured slowly with stirring onto 150 ml. of crushed ice, containing 16 ml. of concentrated sulfuric acid. The resulting precipitate of the 21-hemisuccinic acid is filtered and washed well with water until free from sulfuric acid.

(b) Preparation 0] 9w Zl0r0-16ot,17a-iSOPIOPJ'lid6IZ8dioxy-5a-pregnane-115,21-di0l-3,20-di0ne Ill-sodium hemisuccinate.500 mg. of the ZI-hemisuccinic acid obtained in step a is dissolved in a minimum of 95% alcohol and the resulting solution is neutralized with 0.1 N sodium hydroxide solution. The neutralized solution is freed from alcohol in vacuo, extracted with chloroform to remove residual unneutralized acid and the aqueous solution lyophilized in high vacuum. The residual material represents the pure soduim salt.

EXAMPLE 71 Following the procedure of Example 70 but substituting 10 g. of phthalic anhydride for the succinic anhydride in step a, there is obtained 9u-fiuoro-16a,17a-isopropylidenedioxy-Sa-pregnane-l1fi,21-diol-3,20-dione 21-sodium o-hemiphthalate.

EXAMPLE 72 Acetophenane Derivative 0f 9u-Flu0ro-5a-Pregnane-11a,- 16a,1 701,21-Tetr0l-3,20-Di0ne 21-S0dium H emisuccinate Following the procedure of Example 70 but substituting 4 g. of the acetophenone derivative of 9a-fluoro-5apregnane-11f ,16a,l7a,21-tetrol-3,20-dione for the 90:- fluoro 16a,17m isopropylidenedioxy 5a pregnane- 1lB,21-diol-3,20-dione in step a, the acetophenone derivative of 9u-fiuoro-5a-pregnane 11 8,16a,17oc,21-tetrol-3,20- dione 2l-sodiun1 hemisuccinate is obtained.

EXAMPLE 73 90c Fl0ro-16a,17m Isopropylidenedioxy 5a Pregnane- 11.B,-21-Di0l-3,20-Di0ne 21-P0tassium H emiglumrate Following the procedure of Example 70 but substituting 10 g. of glutaric anhydride for the succinic anhydride in step a, and 0.1 N aqueous potassium hydroxide for the sodium hydroxide in step b, there is obtained 9a-fluoro- 1611,1702 isopropylidenedioxy 50!. pregnane 1113,21- diol-3,20-dione 21-potassium hemiglutarate.

EXAMPLE 74 Following the procedure of Example 1 but substituting 10 g. of 16a,17a-isopropylidene 9a,21-difiuoro-A -preg- Car 1 r J- nadiene-l1B,16e,17a-triol-3,20-dione for the triamcinolone acetonide, 9a,2l-difluoro-16a,17a-isopropylidenedioxy-5a-pregnane-l1B-ol-3,20-dione is obtained.

EXAMPLE 75 9a-Flu0r0-21-Chlore-16nd7a-Is0pr0pylidenedi0xy- Su-Pregnane-I1fi-0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 9oc-fluoro-21-cbloro-A -pregnadiene-1 15,161,170:- triol-3,20-dione 16,17-acetonide for the triamcinolone acetonide, 9a-fiuoro-21-chloro-16a,l7u-isopropylidenedioxy-5a-pregnane-11fi-ol-3,20-dione is obtained.

EXAMPLE 76 BiS-(9a-Flu0rO-16ocJ 7a-Is0pr0pylidenedioxy-5-Pregnane- 11fl,21-Diol-3,20-Di0ne) 21,21'-Sulfite Following the procedure of Example 1 but substituting 10 g. of bis fitriamcinolone -.l6,.l7-acjietonide) 21,21- sulfite for the triamcinolone acetonide, bis-(9a-fiuoro- 1641,17 isopropylidenedioxy 50c pregnane 11fi,21- diol-3,20-dione) 21,21-sulfite is obtained.

EXAMPLE 77 Bis-(9a-Flu0r0-16a,1 7a lsopropyl id en edioxy-S u-Pregname-11,8,21-Di0l-3,20-Di0ne) 21,21 '-Carbonate Following the procedure of Example 1 but substituting 10 g. of bis-(triamcinolone l6a,l7a-acetonide) 21,21- carbonate for the triamcinolone acetonide, bis-(9a-fiuoro- 16,l7a isopropylidenedioxy 50c pregnane 1113,21- diol-3,20-dione) 21,2l-carbonate is obtained.

EXAMPLE 78 Bis-(9u-Flu0r0-1 6 0a,] 7 u-lsopropyl id en edioxy-S a-Pregnan e-1 13,21 -D fol-3 ,2 0-D ione) 21 ,21 -S ul fate Following the procedure of Example 1 but substituting 10 g. of bis-(triamcinolone 160:,17a-21C6t0nid6) 21,21- sulfate for the triamcinolone acetonide, bis-(9a-fiuoro- 1604,1711 isopropylidenedioxy 5a pregnane 115,21- diol-3,20-dione) 2l,21-sulfate is obtained.

EXAMPLE 79 Bis-(9a,Fluor0-16u,17a-Is0pr0pylidenedioxy-Sa-Pregnane- 11[3,21-Di0l-3,20-di0ne) 21,21 -Phenylph0sph0nate Following the procedure of Example 1 but substituting 10 g. of bis-(triamcinolone l6tx,17a-acet0nide) 21,21- phenylphosphonate for the triamcinolone acetonide, bis (90: fluoro 16a,17u. isopropylidenedioxy) 5a pregnane-l1,3,21-diol-3,20-dione) 21,21-phenylphosphonate is obtained.

EXAMPLE 80 9a-Flu0r0-16a,1 7a-1s0pr0pyIidenediOxy-Sa-Pregnan e- 11/3,21-Diol-3,20-Di0ne 21 -Potassium Phosphate To a mixture of 3 ml. of anhydrous pyridine and 0.15 ml. of phosphorous oxychloride maintained at -15 is added dropwise over a ten minute period to a solution of 200 ml. of 9ot-fltlOIO-l60,17a-iSOPI'OPYIidEHCdiOXY-Sar pregnane-1lfl,21-diol-3,20-dione in 3 ml. of pyridine. The resulting solution is allowed to remain at -l5 for an additional 20 minutes at which time 0.2 ml. of water is added and the mixture is allowed to warm up to room temperature. One hour after the addition of water, the solution is concentrated in vacuo to about 2 ml., diluted with 10 ml. of water, extracted with chloroform and ad justed to a pH of 6.8 with potassium carbonate solution. The neutralized solution is lyophilized, triturated with alcohol and the alcoholic solution concentrated to small volume. The potassium salt of 9u-fluoro-16a,l7u-isopropylidenedioxy 5a pregnane-11p,21-diol-3,20-dione 21- phosphate crystallizes under these conditions.

EXAMPLE 81 Following the procedure of Example 1 but substituting 17 10 g. of 6a-fluorotriamcinolone acetonide' for the triamcinolone acetonide, 6a,9a-difluoro-16a,17a-isopropylidenediOXy-Saregnane 115,21 diol-3,20-dione is obtained.

EXAMPLE 82.

6 a,9a-Diflur0-J 6 0a,] 7 a-ISOprOpyZidenediOxy-S a- Pregnane-11/i,21 -Di0l-3 ,20-Di one 21 -Acetate Following the procedure of Example 1 but substituting 10 g. of 16a,17u-isopropylidene 6tx-fiuorotriamcinolone ZI-acetate for the triamcinolone acetonide, 60,90c-difl1l010- 16a,,17u-isopropylidene dioxy a pregnane-11fl,21-di0l- 3,2=0-dione 21-acetate is obtained.

EXAMPLE 83 Following the procedure of Example 1 but substituting g. of 16u,17a-(2'-'butylidene) 6a-fluorotriamcinolone for the triamcinolone acetonide, 6a,9ot-difl1lOIO-l60c,l7a- (2'-butylidenedioxy) Saregnane-I1,8,21-diol-3,20-di0ne is obtained. 7

EXAMPLE 84 Following the procedure of Example 1 but substituting 10 g. of 160:,1704 (4'-methyl-2'-penty1idene) 6u-fluorotri a mcinolone {for the triamcinolone acetonide, 6a,9a-diiiuoro 16w170t (4'-methyl 2' pentylidenedioxy)-5apregnane-l1 8,21-diol-3,20dione is obtained.

EXAMPLE 85 V Following the procedure of Example 1 but substituting 10 g. of 16a,17a-cycl0hexylidene 6a-fluorotriamcinolone for the triamcinolone acetonide, 6a,9 x-difluoro-16u,17acyolohexylidenedioxy 5a pregnane-11,B,21 diol-3,20- dione is obtained.

EXAMPLE 86 6a,9a-DifluOr0-] 6a,] 7oc- (3 -Pentylidenedi0xy 5a- Pregnane-11B,21 -Diol-3,20-Dione Following the procedure of Example 1 but substituting 10 g. of 16a,,17u(3-pentylidene) 6a-fluorotriamcinolone for the triamcinolone acetonide, 6a,9a-difiuoro-16a,17a- (3'-pentylidenedioxy)-5a-pregnane 1113,21 diol 3,20- dione is obtained.

EXAMPLE 87 Following the procedure of Example 1 but substituting 10 g. of 16a,17u-ethylidene 6a-fluorotriamcinolone for the triamcinolone acetonide, 6a,9a.-difluoro 16u,17 x ethylidenediOXy-Suregnane 115,21 diol 3,20-dione is obtained.

EXAMPLE 88 6 oc-FlZlOrO-I 6 ,1 7 a-IsOprOpyZidenediOxy-S a-Pregnane- 11,8,21-Di0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 16u,17a-isopropylidene 6a.fluoro-16a-hydroxyprednisolone for the triamcinolone acetonide, 6oc-fltb0r0- 16a,17a isopropylidenedioxy 5a pregnane 11,8,21- diol-3,20-dione is obtained.

EXAMPLE 89 6 oc-Fluoro-9ot-Methy l--] 6 00,1 7 ot-lsopropy lidenedioxy- 5 u-Pregnane-I 1 5,21 -Di0l-3,2 0-D ione Following the procedure of Example 1 but substituting 10 g. of 16a,17a-isopropylidene 6ot-flllOI0-90L-II16ti1Yl-160t- 18 hydroxyprednisolone for the triamcinolone acetonide, 6afluoro-9ot-methyl-16a,17a isopropylidenedioxy Soc-pregnane-l1fl,21-diol-3,20-dione is obtained.

EXAMPLE Following the procedure of Example II but substituting 10 g. of 16ot,17a-isopropylidene 6u,9a.-difluoro-A -pregnadiene-l 15,1611,17u-triol-3,20-dione for the triamcinolone acetonide, 6a,9u-difluoro 1641.170: isopropylidenedioxy- 5u-pregnane-1 1fi-ol-3,20-dione is obtained.

EXAMPLE 92 1604,] 7 oc-Ch [oral Derivative of 6 a,9a-D iflu0r0-5 a- Pregame-1118,] 6 (1,] 7 0:,21 -Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the 16u,17oi-chloral derivative of 6a-fluorotriamcinolone for the triamcinolone acetonide, the 16a,170t.- chloral derivative of 6a,9a-difluoro-5ot-pregnane-l15,16, 17 a,21-tetr0l-3,20-dione is obtained.

EXAMPLE 93 Acetophenone Derivative of 6 a,9 x-D ifluoro-S a-Pregnane- 11,B,16a,17a,21-Tetr0l3,20-Dione Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of 6a-fluorotriamcinolone for the triamcinolone acetonide, the acetophenone derivative of 60t,90L-difil10I"O-50t-p16gnan6-11fl,160t,170t,21- tetrol-3,20-dione is obtained.

EXAMPLE 94 Acetophenone Derivative of 6a,9a-Diflu0r0-5a-Pregnane- 11fi,16oz,1 704,21-Tetrol-3,20-Dione-21-Acetat 7 Following the procedure of Example 1 but substituting 10 g. of the acetophenone derivative of 6u-fluorotriamcino lone 21-acetate for the triamcinolone acetonide, the acetophenone derivative of 6a,9a-difluoro-5a-pregnane-1113,16a, 17a,21-tetrol-3,20-dione 21-acetate is obtained.

EXAMPLE 95 Following the procedure of Example 1 but substituting 10 g. of the 16a,17a-a1loxan derivative of Got-fillOI'OtIiamcinolone for the triamcinolone acetonide, the alloxan derivative of 6a,9a-difluoro-Sa-pregnane-11fi,16u,17a,21- tert01-3,20-dione is obtained.

EXAMPLE 96 Dicyclopropyl Ketone Derivative of 6a,9a-Diflur0ro-5a- Pregnane-I l,8,16a,1 7a,21-Tetr0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of the dicyclopropyl ketone derivative of 6a-fluorotriamcinolone for the triamcinolone acetonide, the dicyclopropyl ketone derivative of 6a,9ot-difluoro-5a-pregnane- 11,8,16oz,17a,21-tetr0l-3,20-dione is obtained.

EXAMPLE 97 6 a-Chloro-9ot-Fluor0-1 6 11,1 7a-Is0pr0ylidenedioxy-Sa- Pregnane-Z1p,21-Di0l-3,20-Di0ne Following the procedure of Example 1 but substituting 10 g. of 6a-chloro-9tx-fluoro-16a-hydroxyhydrocortisone 19 acetonide for the triamcinolone acetonide, 6a-chl010-9ocfiuoro 160:,17oc isoproylidenedioxy 5a pregnanel1;3,2l-diol3,20-dione is obtained.

The compounds of this invention can also be prepared by the second process of this invention, which is applicable for the preparation of all the compounds of this invention. This process is illustrated by the following example employing l6a-hydroxyhydrocortisone as the starting material.

EXAMPLE 98 16051711 lsopropylidenedioxy 5a Pregnane 1113,21- Dial-3,20-Dine (a) Preparation of Su-pregImne-IIB,16o,17a,21-tetrol- 3,20-dione.-Following the procedure of Example 1 but substituting 9 g. of l6u-hydroxyhydrocortisone for the triamcinolone acetonide, Saregnane-Ilfi,16a,l7a,21- tetrol-3,20-dione is obtained.

(b) Preparation of 16a,]7a-is0pr0pylidinedioxy-Sapregnane-l1fi,21-diol-3,20-di0ne.-To a suspension of 500 mg. of a-pregnane-l15,16a,l7rx,2l-tetrol-3,20-dione in 75 ml. of acetone is added 0.05 ml. of 72% perchloric acid and the mixture is agitated at room temperature for three hours. The mixture is then neutralized with dilute bicarbonate and the acetone removed in vacuo. The resulting crystalline suspension is filtered and the crystals washed with water.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of steroids of the general formula CHzZ wherein R is hydrogen, R is B-hydroxy and together R and R is keto; and X' are each selected from the group consisting of hydrogen, chloro, fluoro and lower alkyl, at least one of the substituents X and X being selected from the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of hydrogen and methyl; Y is selected tom the group consisting of hydrogen, halogen, and lower alkyl; Z is selected from the group consisting of hydrogen, chloro, fluoro, hydroxy and acyloxy; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q are selected from the group consisting of cycloalkyl and monocyclic heterocyclic.

2. 16a,17a-1ower alkylidene 9a-fluoro-5a-pregnane-llfl, 16a,l7a,2l-tetrol-3,20-dione, wherein the alkylidene radical contains at least two carbon atoms.

3. 9oz fluoro 16a,17m isopropylidenedioxy 5apregnane-l1a,21-dio1-3,20-dione.

4. l6oz,17a-1OW61 alkyliden 6u,9a-difluoro-5a-pregnane-llfi,16a,17a,21-tetrol-3,20-dione, wherein the alkylidene radical contains at least two carbon atoms.

5. 600,90: difiuoro l6u,17a isopropylidenedioxy- 5 zx-pregnane-l l 5,2 l-diol-3,20-dione.

6. 16a,l7u-lower alkylidene 12a-fluoro-5a-pregnane- 115,160,l7a,2l-tetrol-3,2O-dione, wherein the alkylidene radical contains at least two carbon atoms.

7. 12a fluoro :,170: isopropylidenedioxy 5apregnane-l1fi,21 diol-3,20-dione.

8. 9oz fiuoro 5a pregnane 1l}3,l6oc,17a tetrol- 3,20-dione 16,1 7-acetophenonide.

9. 6a fluoro 16a,17a isopropylidenedioxy 5apregnane-l1fi'21-diol-3,20-dione.

Bernstein et al., J.A.C.S., vol. 81 (Sept. 5, 1959), pp. 4573 and 4574.

' ERNEST W. SWIDER UNITED STATES PATENT. OFFICE CERTIFICATE OF CORRECTION Patent No. 3,053,836 September 11, 1962 Josef Fried It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 58, strike out "and R are keto; X and X are hydrogen, chloro, fluoro"; column 6, line 48, for 'uantitative" read quantitative column 8, line 5, after "Example" insert l lines 21 and 22, for "l6d,l7@(3 =-Penty1idenedioxy)l2q-Chloro5d-Pregnane-l1 13-01-3,2O-Dione", in italics, read 9q-Fluorol6(1,l7q-Isopropylidenedioxy5 1Pregnane-l],6 Ol3,20-Di0ne in italics; column 19, line 46, after "ket0;" insert X column 20, line 24, for "llu" read 11,6

Signed and sealed this 5th day of February 1963.,

(SEAL) Attest;

DAVID L. LADD Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE GENERAL FORMULA 